Nitric oxide "at heart": emerging paradigms after a decade.
; MASSION, Paul ;
in Archives des Maladies du Coeur et des Vaisseaux (2005), 98(3), 242-8
Despite the apparent redundancy of NOS isoforms in the myocardium, subcellular compartmentation dictates specific NO signaling from each isoform to colocalized effectors in response to physical (e.g ... [more ▼]
Despite the apparent redundancy of NOS isoforms in the myocardium, subcellular compartmentation dictates specific NO signaling from each isoform to colocalized effectors in response to physical (e.g. stretch) or receptor-mediated stimuli. Genetic deletion or overexpression experiments helped to characterize each isoform's respective role in the normal or diseased heart. eNOS and nNOS both contribute to sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart. They also negatively modulate the beta1-/beta2-adrenergic increase in inotropy and chronotropy, and reinforce the (pre- and post-synaptic) vagal control of cardiac contraction, thereby protecting the heart against excessive stimulation by catecholamines. In the ischemic and failing myocardium, iNOS expression is induced and further contributes to attenuate the inotropic effect of catecholamines, as does eNOS coupled to overexpressed beta3-adrenoceptors. nNOS expression also increases in the aging and ischemic heart, but its role (compensatory or deleterious) remains to be defined. Many drugs currently used for the treatment of ischemic or failing cardiac diseases also activate and/or upregulate eNOS in the myocardium, which supports its proposed protective role, e.g. as "endogenous beta-blocker". Future pharmacologic modulation of the cardiac NOS will have to take into account their specific modulation of the various aspects of cardiac function, if one hopes to deliver more targeted and efficient therapy than currently achieved with exogenous NO donors. [less ▲]Detailed reference viewed: 5 (0 ULg)
Nitric oxide and the heart: update on new paradigms.
; MASSION, Paul ; et al
in Annals of the New York Academy of Sciences (2005), 1047
The role of nitric oxide (NO) as a regulator of cardiac contraction was suggested in the early nineties, but a consensual view of its main functions in cardiac physiology has only recently emerged with ... [more ▼]
The role of nitric oxide (NO) as a regulator of cardiac contraction was suggested in the early nineties, but a consensual view of its main functions in cardiac physiology has only recently emerged with the help of experiments using genetic deletion or overexpression of the three nitric oxide synthase (NOS) isoforms in cardiomyocytes. Contrary to the effects of exogenous, pharmacologic NO donors, signaling by endogenous NO is restricted to intracellular effectors co-localized with NOS in specific subcellular compartments. This both ensures coordinate signaling by the three NOS isoforms on different aspects of the cardiomyocyte function and helps to reconcile previous apparently contradictory observations based on the use of non-isoform-specific NOS inhibitors. This review will emphasize the role of NOS on excitation-contraction coupling in the normal and diseased heart. Endothelial NOS and neuronal NOS contribute to maintain an adequate balance between adrenergic and vagal input to the myocardium and participate in the early and late phases of the Frank-Starling adaptation of the heart. At the early phases of cardiac diseases, inducible NOS reinforces these effects, which may become maladaptive as disease progresses. [less ▲]Detailed reference viewed: 5 (0 ULg)
Nitric oxide: does it play a role in the heart of the critically ill?
MASSION, Paul ; ;
in Current Opinion in Critical Care (2001), 7(5), 323-36
Nitric oxide regulates many aspects of myocardial function, not only in the normal heart but also in ischemic and nonischemic heart failure, septic cardiomyopathy, cardiac allograft rejection, and ... [more ▼]
Nitric oxide regulates many aspects of myocardial function, not only in the normal heart but also in ischemic and nonischemic heart failure, septic cardiomyopathy, cardiac allograft rejection, and myocarditis. Accumulating evidence implicates the endogenous production of nitric oxide in the regulation of myocardial contractility, distensibility, heart rate, coronary vasodilation, myocardial oxygen consumption, mitochondrial respiration, and apoptosis. The effects of nitric oxide promote left ventricular mechanical efficiency, ie, appropriate matching between cardiac work and myocardial oxygen consumption. Most of these beneficial effects are attributed to the low physiologic concentrations generated by the constitutive endothelial or neuronal nitric oxide synthase. By contrast, inducible nitric oxide synthase generates larger concentrations of nitric oxide over longer periods of time, leading to mostly detrimental effects. In addition, the recently identified beta3-adrenoceptor mediates a negative inotropic effect through coupling to endothelial nitric oxide synthase and is overexpressed in heart failure. An imbalance between beta 1 and beta2-adrenoceptor and beta3-adrenoceptor, with a prevailing influence of beta3-adrenoceptor, may play a causal role in the pathogenesis of cardiac diseases such as terminal heart failure. Likewise, changes in the expression of endothelial nitric oxide synthase or inducible nitric oxide synthase within the myocardium may alter the delicate balance between the effects of nitric oxide produced by either of these isoforms. New treatments such as selective inducible nitric oxide synthase blockade, endothelial nitric oxide synthase promoting therapies, and selective beta3-adrenoceptor modulators may offer promising new therapeutic approaches to optimize the care of critically ill patients according to their stage and specific underlying disease process. [less ▲]Detailed reference viewed: 4 (1 ULg)